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Antioxidants: Bad for the heart?

Researchers from the University of Washington
have reported that
patients taking antioxidant vitamins in addition to statin and niacin therapy
failed to increase their HDL cholesterol (the "good" cholesterol) as
much as patients not taking antioxidants. These results, reported in
the August 9, 2001 issue of Arteriosclerosis, Thorombosis, and Vascular Biology,
are but the latest in a series of disappointing results in trials examining the
ability of antioxidants to prevent heart disease.

Why antioxidants sound so attractive

It is known that the oxidation of LDL cholesterol contributes to the blood
vessel damage that causes coronary artery disease and heart attacks. By
helping to prevent the oxidation of LDL cholesterol (or, in scientific parlance,
by reducing "oxidative stress,") it has long been believed that
antioxidant supplements like vitamins E and C might help slow or even prevent
the formation of plaques within coronary arteries. Indeed, several
epidemiological studies have been published that seem to confirm that
antioxidant vitamins can reduce the incidence of cardiac events such as heart
attacks or the need for bypass surgery. So: the theory behind antioxidants
has seemed sound, and several studies seem to confirm their effectiveness.
As a result, millions of individuals (including many doctors) now routinely take
vitamin E and C supplements.

Randomized trials have not been kind to antioxidants

Unfortunately, epidemiological studies are considered suboptimal for deciding
whether a therapy works. In epidemiological studies, a population of
patients is followed for a period of time, keeping track of which patients
happen to be using the therapy in question and which do not. Outcomes are
then compared between patients using and not using the therapy. Because
there may be inherent (but unidentified) differences between those who use a
therapy and those who do not, and because patients who choose to use a therapy
might experience improvement due to a "placebo effect," such studies
are regarded as offering suggestive evidence, but not proof, of a treatment's
effectiveness. (With a placebo effect, a "treatment" that
actually has no specific physiological benefit produces positive results because
patients expect it to. The placebo effect is now recognized as sometimes
being quite powerful in alleviating symptoms, and has confounded the evaluation
of countless therapies in medicine.)

To "really" measure a treatment's effectiveness, randomized trials
are usually considered necessary. In randomized trials, groups of
"identical" patients (that is, as close to identical as possible) are
randomly chosen to receive the treatment in question - those who are not
randomized to receive the treatment are given placebo. Ideally, neither
the patients nor their doctors are aware of whether they are actually receiving
the treatment or the placebo. Randomized trials, then, at least in theory,
minimize any hidden, systematic differences between patients taking or not
taking the treatment being studied, and eliminate any falsely positive outcomes
that may result from a "placebo effect" (since patients taking either
the actual treatment or the identical-appearing placebo ought to have the same
degree of placebo effect.)

During the last two years, a number of randomized trials using antioxidant
vitamin supplements have finally been reported, and the results have generally
been disappointing. Because of the failure of randomized trials to
demonstrate a benefit from taking antioxidants, both the American Heart
Association and the Institute of Medicine have released recent statements saying
that, while a diet rich in antioxidant vitamins seems prudent, there is
insufficient evidence to recommend using supplements of of vitamin C, vitamin E,
beta-carotine, selenium, or other antioxidants to prevent heart disease.

The latest study suggests the possibility of harm

The study from the University of Washington, reported last week, brings up
the possibility that antioxidant therapy may do more than merely fail to halt
the progression of coronary artery disease. This new study suggests the
possibility of harm.

In this trial, patients with coronary artery disease who also had low levels
of HDL cholesterol were randomly assigned to one of 4 groups: 1) low-dose statin
and niacin therapy; 2) low-dose statin and niacin therapy plus a cocktail of
antioxidants; 3) a cocktail of antioxidants without statin and niacin, and 4)
placebo. The cocktail of antioxidants consisted of vitamin E, vitamin C,
beta-carotene, and selenium.

The study results showed that the increase in HDL levels seen in patients
receiving statin-niacin therapy was eliminated when they also received the
antioxidants. That is, in these patients the antioxidants were potentially
harmful.

As it turns out, this "negative" finding is less than statistically
perfect. (The finding that antioxidants would reduce HDL levels was not
postulated ahead of time by the investigators, but instead was discovered in a
routine review of their data, bringing up the possibility that the reported
finding was a random data error instead of an actual physiologic
phenomenon.) But the primary endpoints of the study also suggest that
antioxidants blunt the benefits seen with statin-niacin therapy. (While
patients receiving statin-niacin had a 4% reduction in coronary artery blockage,
those who received antioxidants in addition to statin-niacin had a 7% increase
in blockage. In contrast, those receiving antioxidants alone had a 15%
increase in blockage, and those receiving placebo had a 34% increase in
blockage.)

The bottom line: this new study seems to validate the unpopular stance on
antioxidant supplements taken by both the American Heart Association and the
Institute of Medicine.

What to do about antioxidants

DrRich is sorry to say that he must agree with the policy statements of the
AHA and the IOM. So far, there is insufficient data from well-designed
randomized trials to issue a general recommendation for people to take
supplements of the antioxidant vitamins in order to prevent heart disease.
Eating lots of fruits and vegetables - in other words, a good diet - seems the
most prudent course at the moment.

But are antioxidants actively harmful? Based on data from randomized
trials completed to date, it is likely that they are usually not harmful.
But it does seem prudent to recommend that - especially if statins and niacin
are being used in the attempt to increase HDL levels - either antioxidant
supplements should be avoided, or at the very least, HDL levels should be
remeasured both with and without antioxidant supplementation, in order to
document whether those supplements are blunting the benefits of statin-niacin
therapy.